The present invention refers to benzo[c]quinolizine derivatives of general formula (I) 
wherein:
R1, R2, R3, R4, R6, same or different, are chosen in the group consisting of: H, C1-8alkyl, C2-8alkenyl, C2-8alkinyl, cycloalkyl, aryl, heterocycle, halogen, CN, azide, NRRxe2x80x2, C1-8alkylamino, arylamino, C1-8alkyloxy, aryloxy, COOR, CONRRxe2x80x2 wherein R and Rxe2x80x2, same or different, are chosen in the group consisting of: H, C1-8alkyl, cycloalkyl, aryl, heterocycle, arylC1-8alkyl;
R5 is chosen in the group consisting of: H, C1-8alkyl, COOR, CN, aryl, heterocycle;
X is chosen in the group consisting of: O, C(xe2x95x90O)R, COOR, NO2, CONR""R wherein R and Rxe2x80x2 are as above defined;
Q is chosen in the group consisting of: simple bond, C1-8alkyl, C2-8 alkenyl, C2-8alkinyl, cycloalkyl, CO, CONR, NR, wherein R is as above defined;
W is chosen in the group consisting of: H, C1-8alkyl, C2-8alkenyl, C2-8 alkinyl, cycloalkyl, trifluoromethyl, C1-8alkoxy, C1-8alkoxy-C1-8alkyl, arylC1-8alkyl, aryl, aryloxy, arylamino, C1-8alkylcarbonyl, arylcarbonyl, halogen, CN, NRRxe2x80x2, C1-8alkylamino, heterocycle wherein the groups alkyl, alkenyl, alkinyl, cycloalkyl, aryl, heterocycle, can be substituted;
n is an integer comprised between 1 and 4; the symbol ------ means that the corresponding bonds a, b, c, d e, f, and g can be simple or double bonds;
with the proviso that when b or f are a double bond then the group R5 is absent; and with the proviso that the following two compounds are excluded: 4-carbonitril-2,3-dihydro-(1H)-benzo[c]quinolizin-3-one and 3,4-dihydro-1-phenyl-4aH-benzo[c]quinolizin-3-one;
their pharmaceutically acceptable salts or esters, their process for preparation and their use as inhibitors of steroid 5alpha-reductases (hereinafter indicated as 5alpha-reductases).
The invention refers also to compounds of formula (4) 
wherein W, Q, n, R3, R4, R5 are as above defined and Z is a protecting group for the amide-group with the proviso that when R3=R4=R5=(WQ)n=H than Z is not a group ethoxycarbonyl.
The enzyme known as steroid 5alpha-reductase is a system formed by two iso-enzymes (type I and type II or 5alphaR-I and 5alphaR-II respectively)) which converts testosterone into dihydrotestosterone, the most powerful androgen circulating in the body.
The type I iso-enzyme (5alphaR-I) is mainly present in liver and skin while the type II iso-enzyme (5alphaR-II) is mainly present in the prostate tissue and in the male sexual organs and its activity is essential in the fetal developping process for the differentiation of the external sexual organs.
The production of dihydrotestosterone is associated with some pathologies which are widely diffused as for example benign prostate hypertrophy, prostate cancer, baldness and acne in men and hirsutism in women. More particularly iso-enzyme I plays a role in the pathologies regarding the skin while iso-enzyme-II is involved in prostate pathologies.
In the recent years a lot of international searchers have tried to isolate new compounds capable of inhibiting the 5xcex1-reductase enzyme in order to treat the above said pathologies, especially, if possible, acting selectively on only one of the two iso-enzymes.
Inhibitors of 5xcex1-reductase, and also of the iso-enzymes 5xcex1R-I and 5xcex1R-II were already described, for example finasteride used with success in the treatment of benign prostate hypertrophy [see for example J.Med.Chem. 36, 4313-15 (1993), J.Med.Chem. 37, 3871-74 (1994)]. It is therefore evident the importance of developing new compounds capable of inhibiting the action of the 5xcex1-reductase enzyme and in particular capable of acting selectively on 5xcex1R-I iso-enzyme which, as said, is responsible, of widely diffused pathologies having an high impact as baldness in men and hirsutism in women.
The present invention refers to new compounds capable of inhibiting the 5xcex1-reductase enzyme, either selectively in respect of 5xcex1R-I and 5xcex1R-II or on both the iso-enzymes, useful for the treatment of the pathologies mediated by the enzyme.
The products according to the invention have general formula (I) 
wherein the substituents R1, R2, R3, R4, R5, R6, X, Q, W, n and the symbol ----- are as above defined.
According to the present invention with group C1-8alkyl, C2-8alkenyl and C2-8alkinyl are indicated linear or branched alkyl radicals as for example: methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, ethylene, propene, butene, isobutene, acetylene, propine, butine ecc.
With cycloalkyl are indicated: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, canphane, adamantane.
With aryl are indicated: phenyl and naphtyl. Heterocycle means in particular: saturated or aromatic heterocycles containing one or more N atoms, more particularly: piridine, imidazole, pyrrole, indole, triazoles, pyrrolidine, piperidine. Halogen means: fluorine, chlorine, bromine, iodine.
The substituents of the above said group W are preferably: halogen, OR, phenyl, NRRxe2x80x2, CN, COOR, CONRRxe2x80x2, C1-8alkyl (wherein R and Rxe2x80x2 are as above defined).
In particular, according to the present invention compounds of formula (I) are preferred wherein:
R5=H, heterocycle
Xxe2x95x90O
Q=simple bond, CO, CONR, NR (wherein R is as above defined) W=H, F, Cl, Br, Me, t-butyl, C1-8alkoxy, 2,5-dimethylhexyl, trifluoromethyl, 2,5-(di-trifluoromethyl)-phenyl, 4-methoxy-phenyl, 4 -fluoro-phenyl, phenyl, phenyl-C1-8alkyl, C1-8alkylcarbonyl, phenylcarbonyl.
n=1 and 2
R1, R2, R3, R4, R6=H, Me, CN, phenyl, COOR, CONRRxe2x80x2 (wherein R and Rxe2x80x2 are as above defined).
Among the pharmaceutically acceptable esters and salts according to the present invention the following can be mentioned: hydrochloride, sulphate, citrate, formiate, phosphate.
Preferred compounds according to the present invention are:
1,2,4,4a,5,6 hexahydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-1,2,4,4a,5,6 hexahydro-(11H)-benzo[c]quinolizine-3-one;
1,2,4,4a,5,6 hexahydro-8-methyl-(11H)-benzo[c]quinolizine-3-one;
1,2,4,4a,5,6 hexahydro-4-methyl-(11H)-benzo[c]quinolizine-3-one;
1,2,4,4a,5,6 hexahydro-1-methyl-(11H)-benzo[c]quinolizine-3-one;
1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
1-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
5,6-dihydro- (11H)-benzo[c]quinolizine-3-one;
8-chloro-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-1-methyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-methyl-4,4a, 5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4-methyl-4,4a,5,6tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis) and (trans);
8-chloro-4-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4,8-dimethyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4,8-dimethyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis) and (trans);
8-chloro-4-methyl-4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis) and (trans).
The compounds according to the present invention can be prepared for example starting from compounds of formula 2
wherein R3, R4, W, Q and n are as above defined, following the reaction Scheme reported hereinafter.
The compounds 2 are commercialy available or can be prepared according to known techniques.
As it can be seen from the Scheme the preparation of the compounds according to the invention involves the protection of the amide-group in compound 2 by the protecting group Z, for example tert-butoxycarbonyl (t-Boc), to give compound 3; compound 3 is reduced to compound 4, for example (when R5 is H) with sodium borohydride in ethanol (pH 3), which is reacted with a silylether 6, produced xe2x80x9cin situxe2x80x9d starting from vinyl-ketones 5 (wherein R1, R2 and R6 are as above defined) with a silylating agent as trimethylsilyltrifluorometansulphonic anhydride (TMSOTf) and thereafter hydrolized, for example in sodium hydrogencarbonate, to give the compounds of formula (I) wherein X=0. The possible introduction of the double bonds and the transformation of the group X in one of the other groups mentioned above can be easily performed according to known techniques starting from the corresponding compound of formula (I) obtained as indicated. For example the introduction of the double bonds in position a or b, can be performed by reaction of dichlorodicyanoquinone (DDQ) with the corresponding silylenolethers or by oxidation with mercuric acetate of the saturated corresponding compound obtained as described above. The transformation of group X can be performed via the corresponding enoltriflates and their carbonylation in the presence of palladium diacetate, triphenylphosphine and the suitable nucleophilic reagent (alcohol, amine, nitro-group).